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The goal of this study project is to better understand the intricate relationship between the anti- inflammatory medication flurbiprofen and the mutant variation S20K of Islet Amyloid Polypeptide (IAPP) aggregation. Examining the structural subtleties that impact toxicity, the study explores the single-stranded structural inclinations of wild-type hIAPP prior to aggregation. The effect of the S20K mutation, which is known to obstruct amyloid production, on fibril shape and kinetics will be investigated. The study also looks into flurbiprofen's dual function as an IAPP aggregation accelerator and inhibitor. The investigation also looks at smaller chemicals in an effort to find ones that, when combined with flurbiprofen, can prevent the formation of amyloid fibrils. With the ultimate goal of creating a small molecule medication to stop the production of amyloid fibrils in people with type 2 diabetes, attention is increasingly focused on comprehending the molecular processes underlying the inhibitory actions of these molecules. 3.1) Identify small compounds that can prevent the development of amyloid fibrils by S20K IAPP in the presence of flurbiprofen. The primary goal is to methodically investigate a wide variety of tiny chemicals that can stop the S20K mutant of Islet Amyloid Polypeptide (IAPP) from forming amyloid fibrils, especially when flurbiprofen is present. Thioflavin-T tests will be the main focus of a comprehensive library of chemical compounds that will be painstakingly screened utilizing a variety of biophysical approaches in order to accomplish this. By identifying substances that show an inhibitory impact on the aggregation process, these tests offer a dependable way to track the production of amyloid. Thioflavin-T fluorescence variations will be closely monitored while the S20K mutant IAPP is exposed to the chosen drugs, including flurbiprofen, as part of the screening procedure. Compounds with a considerable reduction in fluorescence will indicate inhibited amyloid fibril production, will be studied further. The ability of compounds to synergistically improve the inhibitory effects of flurbiprofen will also be considered in the screening criteria. Apart from Thioflavin-T assays, additional biophysical methods like dynamic light scattering and circular dichroism will be used to obtain a thorough comprehension of the structural changes brought about by the chosen substances. These methods will help distinguish between substances
that actually obstruct fibril production and those that only postpone it. Following identification, the compounds will be subjected to extensive validation and characterisation in order to determine their specificity and effectiveness in suppressing S20K IAPP amyloidogenesis. 3.2) Determine the mechanism of how these small molecules work. The aim is to decipher the complex mechanisms behind the small compounds' inhibitory effect on the Islet Amyloid Polypeptide (IAPP) S20K mutant. Designing focused therapies to prevent the production of amyloid fibrils requires an understanding of the intricate interactions between these tiny molecules and the S20K mutation. Molecular dynamics simulations will be used to model the changing behavior of the small molecules in association with the S20K mutant in an effort to gain these mechanistic insights. Through tracking the dynamic interactions between these drugs and the mutant IAPP as time passes, the aim is to clarify the binding mechanisms, structural modifications, and kinetic landscapes that define their inhibitory effects. NMR spectroscopy will be an essential tool for examining the atomic-level intricacies of these interactions, working in tandem with molecular dynamics simulations. Through the analysis of the S20K mutant's and the small molecules' chemical shifts and relaxation parameters, we will be able to map out the precise binding locations, conformational alterations, and overall structural dynamics involved in suppression. The synthesis of small molecules that are optimized will also be guided by the identification of critical regions and structural motifs that are involved in the interaction. This repeated procedure, which combines computer models and experimental NMR data, strives to refine and improve the compounds' inhibitory capabilities, ultimately facilitating the fabrication of more effective inhibitors. 3.3) Development of a Small Molecule Drug that can be used to prevent the formation of amyloid fibrils by S20K IAPP in people with type 2 diabetes. : The project aims to proceed towards the production of an effective small molecule medication by building on the insights acquired from the recognized small molecules. This goal entails manufacturing and developing chemicals with appropriate inhibitory properties to prevent the
creation of amyloid fibrils by the S20K IAPP, which is particularly significant to persons with type 2 diabetes. The goal is to build the groundwork for a prospective therapeutic intervention in amyloid-related problems. 3.4) Focus on molecules that can target the early stages of amyloidogenesis: Understanding the vital importance of early detection and treatment in amyloidogenesis, this research attempts to focus on compounds that are specially designed to target the early phases of amyloid formation. We want to contribute useful insights that could modify therapeutic tactics by choosing drugs that show efficacy in slowing the initial phases of aggregation. Thorough study will lead the selection and optimization of compounds with a preference for early-stage amyloidogenesis inhibition using Thioflavin-T assays and microscopy techniques. These precise goals create a comprehensive strategy, combining experimental methodologies and cognitive insights, to address the complex issues provided by S20K mutant IAPP and its consequences in amyloid-related illnesses, including type 2 diabetes. 5) Future work 5.1) Testing Toxicity of S20K with & without Flurbiprofen : The aim of the research id to go into a more in-depth examination of the toxicity associated with the S20K mutation in Islet Amyloid Polypeptide (IAPP). The study will try to disentangle the subtle interaction between the S20K mutation and Flurbiprofen in terms of potential harmful effects on pancreatic beta cells by systematically altering Flurbiprofen dosages. The experimental design will include cellular assays such as viability tests and cytotoxicity assessments, as well as the use of relevant cell lines such as INS-1, to provide a thorough understanding of the influence on insulin production and beta-cell health. This method will strive to elucidate dose-dependent effects, shedding light on Flurbiprofen's possible therapeutic function in alleviating cellular damage caused by the S20K mutation. 5.2) Quantitative Analysis of Kinetics : This research will focus on a detailed quantitative understanding of the dynamics of amyloid development. The work attempts to extract subtle temporal information using cutting-edge approaches, enabling a more comprehensive knowledge of the dynamic mechanisms involved in
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IAPP consolidation. This method will allow for a thorough investigation of the time duration of amyloid production, allowing for the discovery of critical milestones and transitions within the aggregation process. The research aims toward contributing to a more detailed characterisation of the fluctuations in time related to amyloidogenesis by refining existing approaches. 5.3) Comparison with Compounds that Inhibit Amyloid Formation : To broaden the scope of the inquiry, this study will include a comparison with known drugs that suppress amyloid development. The research intends to explain unique properties and mechanisms by contrasting the effect of newly found small molecules, including those described in the paper, with recognized inhibitors. This comparative approach will shed light on potential synergistic effects or different routes in the prevention of amyloidogenesis. The research will involve careful analyses that will take into account structural features, binding connections, and effectiveness in preventing amyloid formation. 5.4) NMR to Study Amyloid Inhibitor-Polypeptide Interactions: This research will conduct in-depth studies to uncover the complicated connections among amyloid inhibitors and the polypeptide chain using Nuclear Magnetic Resonance (NMR) spectroscopy. This high-resolution technique will seek to provide molecular-level insights into binding locations, modifications to conformation, and the overall molecular interplay required to prevent amyloid formation. The project will use NMR techniques to explore the structural changes and spatial arrangements driving the relationship between amyloid inhibitors like Flurbiprofen and the Islet Amyloid Polypeptide.

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